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Atezolizumab for PD-L1–Positive Locally Advanced or Metastatic Triple-Negative Breast Cancer


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EARLIER THIS YEAR, atezolizumab was granted accelerated approval in combination with nab-paclitaxel in the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express programmed cell death ligand 1 (PD-L1–stained tumor-infiltrating immune cells of any intensity covering ≥ 1% of the tumor area), as determined by a U.S. Food and Drug Administration (FDA)-approved test.1,2 The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting patients with triple-negative breast cancer for atezolizumab.

Supporting Efficacy Data

Approval was based on findings from the phase III double-blind IMpassion130 trial (ClinicalTrials.gov identifier NCT02425891), which included 902 patients with unresectable locally advanced or metastatic triple-negative breast cancer who had received no prior chemotherapy for metastatic disease.2,3 Patients were randomly assigned 1:1 to receive atezolizumab at 840 mg or placebo intravenous (IV) infusions on days 1 and 15 of every 28-day cycle plus nab-paclitaxel at 100 mg/m2 via IV infusion on days 1, 8, and 15 of every 28-day cycle. Randomization was stratified by the presence of liver metastases, prior taxane treatment, and PD-L1 expression; tumor specimens (archival or fresh) were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory to define the PD-L1–positive population for prespecified analyses. Patients received treatment until radiographic disease progression on Response Evaluation Criteria in Solid Tumors version 1.1 or unacceptable toxicity. Among the 902 patients, 369 (41%) tested positive for PD-L1, including 185 in the atezolizumab group and 184 in the control group.

OF NOTE

Atezolizumab carries warnings/precautions for immune-related pneumonitis, hepatitis, colitis, and endocrinopathies; infections; infusion-related reactions; and embryofetal toxicity.

In the PD-L1–positive population, median progression-free survival was 7.4 months (95% confidence interval [CI] = 6.6–9.2 months) in the atezolizumab plus nab-paclitaxel group vs 4.8 months (95% CI = 3.8–5.5 months) in the control group (stratified hazard ratio = 0.60, P < .0001). The objective response rate was 53%, including complete response in 9%, vs 33%, with complete response in up to 1%. The median duration of response was 9.2 vs 6.2 months. Overall survival data were immature, with deaths having occurred in 43% of the intent-to-treat population.

How It Works

Atezolizumab is a PD-L1–blocking monoclonal antibody that binds to PD-L1 and inhibits its interactions with PD-1 (programmed cell death protein 1) and B7.1 receptors. This action releases the PD-L1/PD-1–mediated inhibition of immune response, including activation of an antitumor immune response without inducing antibody-dependent cellular cytotoxicity. PD-L1 may be expressed on tumor cells or tumor-infiltrating immune cells and can contribute to inhibition of an antitumor immune response in the tumor microenvironment. Binding of PD-L1 to PD-1 and B7.1 receptors on T cells and antigen-presenting cells results in suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

How It Is Used

Patients with locally advanced or metastatic triple-negative breast cancer should be selected for treatment with atezolizumab in combination with nab-paclitaxel based on the PD-L1 expression on tumor-infiltrating immune cells using an FDA-approved test.

The recommended dosage of atezolizumab is 840 mg via IV infusion over 60 minutes, followed by 100 mg/m2 of nab-paclitaxel. In each 28-day cycle, atezolizumab is administered on days 1 and 15, and nab-­paclitaxel is administered on days 1, 8, and 15 until disease progression or unacceptable toxicity. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be delivered over 30 minutes. No dose reductions for atezolizumab are recommended. Infusion should be slowed or interrupted for grade 1 or 2 infusion reactions and permanently discontinued for grade 3 or 4 infusion reactions.

ATEZOLIZUMAB IN TRIPLE-NEGATIVE BREAST CANCER

  • Atezolizumab was granted accelerated approval in combination with nab-paclitaxel in the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1, as determined by an FDA-approved test.
  • The recommended dosage of atezolizumab is 840 mg via IV infusion over 60 minutes, followed by 100 mg/m2 of nab-paclitaxel.

Product labeling provides instructions for managing immune-mediated adverse reactions to atezolizumab. Recommended dosage modifications follow: atezolizumab should be withheld for grade 2 pneumonitis; hepatitis with aspartate transaminase (AST) or alanine transaminase (ALT) > 3 and up to 8 times the upper limit of normal (ULN) or total bilirubin > 1.5 and up to 3 times ULN; grade 2 or 3 diarrhea or colitis; grade 2, 3, or 4 endocrinopathies; other grade 3 immune-mediated events involving a major organ; and grade 3 or 4 infection. Product labeling provides instructions for resuming treatment.

Atezolizumab should be permanently discontinued for grade 3 or 4 pneumonitis; hepatitis with AST or ALT > 8 times ULN or total bilirubin > 3 times ULN; grade 4 diarrhea or colitis; other grade 4 immune-mediated events involving a major organ; persistent grade 2 or 3 adverse reactions that do not recover to grade 0 or 1 within 12 weeks of the last dose; inability to reduce corticosteroid treatment to ≤ prednisone 10 mg/d (or equivalent) within 12 weeks after the last dose; and recurrent grade 3 or 4 adverse reactions.

Safety Profile

The most common adverse events of any grade among 452 patients receiving atezolizumab plus nab-paclitaxel in the IMpassion130 trial were alopecia (among 438 in the safety population of the nab-paclitaxel plus placebo group), peripheral neuropathies, fatigue, nausea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. The most common grade 3 or 4 adverse events in the atezolizumab group were peripheral neuropathies, neutropenia, decreased neutrophil count, fatigue, anemia, hypokalemia, pneumonia, and increased AST.

Serious adverse events occurred in 23% of the atezolizumab group, with the most common being pneumonia, urinary tract infection, dyspnea, and pyrexia. Adverse events led to discontinuation of atezolizumab in 6% of patients, with the most common cause being peripheral neuropathy. Adverse events led to death in six patients in the atezolizumab group.

Atezolizumab carries warnings/precautions for immune-related pneumonitis; immune-related hepatitis; immune-related colitis; immune-related endocrinopathies; infections; infusion-related reactions; and embryofetal toxicity. Patients should be monitored for liver function. Patients should be advised not to breastfeed while receiving atezolizumab. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm633065.htm. Accessed September 20, 2019.

2. Tecentriq (atezolizumab) injection prescribing information, Genentech, Inc, March 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s018lbl.pdf. Accessed September 20, 2019.

3. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.


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